Brain-region-specific changes and dysregulation of activity regulated genes in Gria3 mutant mice, a genetic animal model of schizophrenia

Abstract

Protein-truncating variants in GRIA3 (encoding the GluA3/GluR3 subunit of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors) are associated with substantially increased risk of schizophrenia (SCZ). Here we characterized Gria3 mutant mice carrying a protein-truncating mutation that mimics a SCZ-associated variant. Transcriptomic analysis revealed that activity-regulated genes are downregulated in cortical regions, while immune and glia-related pathways exhibit brain-region-specific changes. The transcriptomic changes in Gria3 mutant mice are remarkably different from those in Grin2a mutant mice, particularly in the prefrontal cortex, even though both encode glutamate receptors and are associated with SCZ risk. Proteomic analysis further demonstrated that loss-of-function of Gria3 profoundly alters the protein composition of synapses. These findings in a genetic mouse model provide potential insights into the pathophysiological mechanisms underlying SCZ.